Charcot–Marie–Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments

• Published in: Acta neuropathologica Vol. 126; no. 1; pp. 93 - 108
• Main Authors: Holmgren, Anne, Bouhy, Delphine, De Winter, Vicky, Asselbergh, Bob, Timmermans, Jean-Pierre, Irobi, Joy, Timmerman, Vincent
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2013; Springer; Springer Nature B.V
• Subjects: Antibodies; Axonal Transport - genetics; Axons - metabolism; Axons - pathology; Cell Line, Tumor; Charcot-Marie-Tooth Disease - genetics; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Cyclin-dependent kinases; Genetic aspects; Heat shock proteins; HSP27 Heat-Shock Proteins - genetics; Humans; Immunoprecipitation; Kinases; Kinesin - metabolism; Laboratories; Medicine; Medicine & Public Health; Molecular Chaperones; Mutation; Mutation - genetics; Nervous system; Neuroblastoma - pathology; Neurofilament Proteins - metabolism; Neurosciences; Original Paper; Pathology; Peripheral neuropathy; Phosphatase; Phosphorylation; Phosphorylation - genetics; Transfection - methods; Belgium; United States > US; Charcot–Marie–Tooth disease; Cyclin-dependent kinase; Neurofilaments; Small heat shock protein; Peripheral neuropathy
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-013-1133-6

Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot–Marie–Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs.